LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma.

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.

Peripheral B cells repress B-cell regeneration in aging through a TNF-α/IGFBP-1/IGF-1 immune-endocrine axis.

Loss of B lymphocyte regeneration in the bone marrow (BM) is an immunologic hallmark of advanced age, which impairs the replenishment of peripheral B-cell subsets and results in impaired humoral responses, thereby contributing to immune system dysfunction associated with aging. A better understanding of the mechanism behind this loss may suggest ways to restore immune competence and promote healthy aging. In this study, we uncover an immune-endocrine regulatory circuit that mediates cross-talk between peripheral B cells and progenitors in the BM, to balance B-cell lymphopoiesis in both human and mouse aging. We found that tumor necrosis factor α (TNF-α), which is increasingly produced by peripheral B cells during aging, stimulates the production of insulin-like growth factor-binding protein 1 (IGFBP-1), which binds and sequesters insulin-like growth factor 1 (IGF-1) in the circulation, thereby restraining its activity in promoting B-cell lymphopoiesis in the BM. Upon B-cell depletion in aging humans and mice, circulatory TNF-α decreases, resulting in increased IGF-1 and reactivation of B-cell lymphopoiesis. Perturbation of this circuit by administration of IGF-1 to old mice or anti-TNF-α antibodies to human patients restored B-cell lymphopoiesis in the BM. Thus, we suggest that in both human and mouse aging, peripheral B cells use the TNF-α/IGFBP-1/IGF-1 axis to repress B-cell lymphopoiesis. This trial was registered at www.clinicaltrials.govas#NCT00863187.

Switching from intravenous tocilizumab to subcutaneous administration during COVID-19 pandemic: impact on treatment efficacy and patient satisfaction.

OBJECTIVES: We aimed to assess the efficacy and patient satisfaction of subcutaneous tocilizumab (SC TCZ) in patients previously treated with intravenous tocilizumab (IV TCZ) during the COVID-19 pandemic. METHODS: We conducted a single-centre retrospective study at the Rheumatology Day Care at the Rheumatology Institute, Rambam Health Care Campus, Israel. Clinical and laboratory data of IV TCZ treated patients who switched to SC TCZ were retracted and analysed. Data were collected from the last two visits before switching to SC treatment and two visits afterwards. A telephone call conversation was conducted for all patients who continued SC treatment and did not come to follow-up visits. RESULTS: Forty patients (age 53.03 (± 15.7)) treated with IV TCZ were switched to SC TCZ in April-May 2020. Three patients were excluded from the study. Most of the patients were treated with TCZ for 6.35 (±2.89) years and had low disease activity. 26/37 (70%) patients discontinued SC TCZ therapy and switched back to IV TCZ. The majority of discontinuations were due to flare up of the underlying disease reflected by increased number of tender and/or swollen joints, prolongation of morning stiffness or increased pain VAS score. Two patients were hospitalised for IV glucocorticoids and 1 patient underwent knee arthrocentesis. 11/37 (30%) patients continued SC TCZ treatment. 3/11 (27%) expressed less satisfaction with SC TCZ therapy. CONCLUSIONS: More than half of the patients who switched from IV TCZ to SC TCZ showed signs of flare of their underlying disease or were less satisfied with SC treatment.

Hypermobility spectrum disorders and active migraine in Israeli adolescents: A nationwide study.

OBJECTIVE: To assess the association between hypermobility spectrum disorders/hypermobile type Ehlers Danlos Syndrome (HSD/hEDS) and migraine in a national sample of adolescents in Israel. BACKGROUND: The association between HSD/hEDS and migraine is unclear, even more so in pediatric populations. METHODS: This population-based, cross-sectional study included 1,627,345 Israeli adolescents (945,519/1,626,407 [58%] males; mean age 17 ± 0.5 years) who were medically assessed before mandatory military service during 1998-2020. Diagnoses of migraine with at least one attack per month (active migraine) and HSD/hEDS were confirmed by certified specialists. The prevalences of active migraine in adolescents with and without HSD/hEDS were computed and the association between HSD/hEDS and active migraine was examined. RESULTS: Active migraine was significantly more prevalent in adolescents with HSD/hEDS (307/4686 [6.5%]) compared to those without HSD/hEDS (51,931/1,621,721 [3.2%]) (OR = 2.16, 95% CI 1.90-2.45). The association between HSD/hEDS and active migraine persisted in a multivariable analysis (OR = 2.08, 95% CI 1.85-2.34) and in several sensitivity analyses. CONCLUSIONS: We found a significant association between HSD/hEDS and active migraine in both male and female adolescents. Clinical awareness of the association can promote early diagnosis and treatment of migraine. Further research is required to identify appropriate pharmacologic and nonpharmacologic migraine treatment strategies for individuals with HSD/hEDS.

Hypermobility spectrum disorders and irritable bowel syndrome: A nationwide study of 1.6 million adolescents.

BACKGROUND AND AIM: The association between hypermobility spectrum disorders/hypermobile type Ehlers-Danlos syndrome (HDS/hEDS) and irritable bowel syndrome (IBS) is yet to be clarified. We aimed to assess this association in a national sample of adolescents. METHODS: A population-based cross-sectional study included 1 627 345 Israeli adolescents (58% male; mean age 17 years) who were medically assessed before compulsory military service during 1998-2020. Diagnoses of HSD/hEDS and IBS were confirmed by board-certified specialists. The prevalence and odds ratios (ORs) for IBS in adolescents with and without HSD/hEDS were computed. RESULTS: A total of 4686 adolescents (2553 male) with HSD/hEDS were identified, of whom 71 were diagnosed with IBS (prevalence = 1.5%). Of the 1 621 721 adolescents in the control group, 8751 were diagnosed with IBS (prevalence = 0.5%). Unadjusted logistic regression revealed a significant association between HSD/hEDS and IBS (OR = 2.16 [95% confidence interval, CI, 1.90-2.45]), which persisted in multivariable adjusted models (OR = 2.58 [95% CI, 2.02-3.24]), and in several sensitivity analyses. The association was evident in both male and female adolescents with ORs of 2.60 (95% CI, 1.87-3.49), and 2.46 (95% CI, 1.66-3.49), respectively. The association was accentuated in a sensitivity analysis accounting for other medical and psychiatric comorbidities. CONCLUSIONS: We found a significant association between HSD/hEDS and IBS in both male and female adolescents. Clinical awareness of the association can promote early diagnosis of IBS and appropriate multidisciplinary treatment. Further research is required to identify the common pathological pathways of the conditions and to develop new IBS treatment strategies for people with HSD/hEDS.

Disease activity and humoral response in patients with inflammatory rheumatic diseases after two doses of the Pfizer mRNA vaccine against SARS-CoV-2.

BACKGROUND: The registration trials of messenger RNA (mRNA) vaccines against SARS-CoV-2 did not address patients with inflammatory rheumatic diseases (IRD). OBJECTIVE: To assess the humoral response after two doses of mRNA vaccine against SARS-CoV-2, in patients with IRD treated with immunomodulating drugs and the impact on IRD activity. METHODS: Consecutive patients treated at the rheumatology institute, who received their first SARS-CoV-2 (Pfizer) vaccine, were recruited to the study, at their routine visit. They were reassessed 4-6 weeks after receiving the second dose of vaccine, and blood samples were obtained for serology. IRD activity assessment and the vaccine side effects were documented during both visits. IgG antibodies (Abs) against SARS-CoV-2 were detected using the SARS-CoV-2 IgG II Quant (Abbott) assay. RESULTS: Two hundred and sixty-four patients with stable disease, (mean(SD) age 57.6 (13.18) years, disease duration 11.06 (7.42) years), were recruited. The immunomodulatory therapy was not modified before or after the vaccination. After the second vaccination, 227 patients (86%) mounted IgG Ab against SARS-CoV-2 (mean (SD) 5830.8 (8937) AU/mL) and 37 patients (14%) did not, 22/37 were treated with B cell-depleting agents. The reported side effects of the vaccine were minor. The rheumatic disease remained stable in all patients. CONCLUSIONS: The vast majority of patients with IRD developed a significant humoral response following the administration of the second dose of the Pfizer mRNA vaccine against SARS-CoV-2 virus. Only minor side effects were reported and no apparent impact on IRD activity was noted.

ACPA Antibodies Titer at the Time of Rheumatoid Arthritis Diagnosis Is Not Associated with Disease Severity.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease with the presence of autoantibodies, rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA). The presence of RF or ACPA predicts RA severity. Data on the influence of ACPA titer on RA course are limited. OBJECTIVES: To determine the correlation between ACPA titers at the time of RA diagnosis to RA features and severity during 3 years of follow-up. METHODS: We performed a retrospective study of RA patients treated at our institution during the years 2006-2015 with known ACPA titers at RA diagnosis who completed at least 3 years of follow-up. Patients (N=133) were divided according to ACPA titer: seronegative (< 15 U/ml, n=55), weakly positive (15-49 U/ml, n=18), moderately positive (50-300 U/ml, n=29), and strongly positive (> 300 U/ml, n=31). Patient data, including disease activity score (DAS28), bone erosion on hand and/or foot X-rays, treatments with corticosteroids and disease-modifying-anti-rheumatic drugs (DMARDs), and hospitalizations, were recorded. Chi-square and Mann-Whitney method were used for statistical analysis. P < 0.05 was considered as statistically significant. RESULTS: Male gender, smoking, and RF positivity correlated with ACPA positivity and higher ACPA titers. There was no correlation between ACPA titer and the variables defined as representing RA severity: higher DAS28, bone erosions, hospitalizations, need for corticosteroids, and conventional and biological DMARDs. CONCLUSIONS: Titer of ACPA was not identified as a predictive factor for RA severity.

The Effects of Adalimumab in Behçet Disease Patients on Clinical Manifestations and on Pro-Inflammatory Cytokines Milieu: Long-Term Follow-Up.

BACKGROUND: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management. OBJECTIVES: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu. METHODS: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies. RESULTS: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2-6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed. CONCLUSIONS: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study.

OBJECTIVE: To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. METHODS: We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. RESULTS: 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). CONCLUSION: Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.

Autoimmune Diseases in Systemic Sclerosis Patients and Their Relatives: Data from a Single Center.

BACKGROUND: The aggregation of autoimmune diseases in relatives (AID-R) of patients with systemic sclerosis (SSc) has been reported. OBJECTIVES: To analyze the prevalence of autoimmune diseases in SSc relatives and to compare their features to those of SSc patients without AID-R (controls). METHODS: A case-control analysis compared SSc patients with AID-R to those without AID-R (25 patients) with similar disease duration. RESULTS: Among 322 patients, 25 (7.7%; 21 females, 41.4 ± 15.6 years of age, disease duration 11 ± 8.6 years) had AID-R (21 had a first-degree relative, 4 had a second-degree relative, and 2 had both). Fourteen patients (56%) and five controls (20%) had an additional autoimmune disease (P < 0.009). Diffuse SSc (48% vs. 24%) and arthritis (72% vs. 28%) were more frequent among the patients with AID-R than the controls (P < 0.05). No significant differences were found regarding lung, heart, vascular, and digestive system involvement. The mean number of additional autoimmune diseases was 0.84 ± 0.94 in AID-R vs. 0.24 ± 0.52 in controls (P < 0.038). The mean number of autoantibodies was 2.8 ± 1.5 and 2.2 ± 0.9 (P < 0.047). Five patients died during follow-up, four of whom had AID-R. Relatives of SSc patients had diverse autoimmune diseases; the prevalence of SSc in scleroderma relatives was 1.86% (2 in first-degree and 6 in second-degree relatives). SSc patients with AID-R had an obvious tendency to polyautoimmunity. CONCLUSIONS: A precise family history is an important clue in prognosis and prediction of autoimmune diseases in SSc patients and their relatives.

[THE EMERGENCE OF RHEUMATOID ARTHRITIS AT THE AGE OF OVER 60 - A COMPARISON OF CLINICAL MANIFESTATIONS AND ACCESS TO TREATMENT PATTERN COMPARED TO YOUNGER PATIENTS].

INTRODUCTION: The aging process of rheumatoid arthritis (RA) requires re-assessment of diagnostic and treatment approaches in patients who developed RA at 60-69 years (EORA-Elderly-Onset RA), 70 years and older (LORA-Late Onset RA) compared with CORA patients - Common Onset RA (35 - 50 years). METHODS: Comparing data of CORA, EORA and LORA patients: gender, nationality; swollen and tender joints (out of 28 joints), Disease Activity Score (DAS28), inflammatory markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA); treatment with corticosteroids and disease modifying anti rheumatic drugs (DMARDs). RESULTS: Patients' files were examined: CORA (39, 33.5%), EORA (37, 30.8%) and LORA (44, 36.7%). No differences were observed between swollen and tender joints, inflammatory markers, DAS28, RF, and ACPA. Methotrexate was introduced in 94.9% of CORA patients versus EORA (77.3%) and LORA (78.4%); 88.6% LORA-patients received corticosteroids versus 69.2% CORA; 43.2% of LORA patients and 92.3% CORA received synthetic disease-modifying antirheumatic drugs (DMARDs); 43.6% CORA versus 16.2% EORA and 9.3% LORA patients received biologics. CONCLUSIONS: No clinical and laboratory differences were found between CORA, EORA, and LORA groups. EORA and LORA patients received less synthetic and biological DMARDs. It is necessary to change the attitude to EORA and LORA and to promote advanced optimal treatments. Prospective studies on the efficacy and safety of novel drugs in EORA and LORA patients are needed.

[THE INPUT OF MEASURING INFLIXIMAB LEVELS AND LEVELS OF ANTIBODIES TO INFLIXIMAB IN THE MANAGEMENT OF PATIENTS WITH RHEUMATIC DISEASES].

BACKGROUND: High levels of infliximab (IFX) directed antibodies (IFX-Ab) may result in significant reduction in IFX concentration and loss of drug efficacy. OBJECTIVES: To assess the input of measuring serum IFX levels and levels of IFX-Ab in the management of rheumatic diseases. METHODS: Serum levels of IFX and anti-IFX-Ab were measured by ELISA (IFX-Abs were also identified by anti-human lambda chain Ab) and correlated to patients (responders and nonresponders) disease activity scores. RESULTS: A total of 144 tests for IFX were performed in 91 patients (mean age 50.2 years and disease duration 9.9 years). Among responders (57 patients) levels (mean, median) of IFX were significantly higher than in non-responders (34 patients) (4.2 mcg/ml (2.3) versus 1.1 mcg/ml (0.45)); levels of IFX-Ab in responders were significantly lower than in non-responders (4.59 mcg/ml (1.0) versus 13.1 (6.1)). High IFX-Ab levels predicted IFX discontinuation in 8.8% of responders and 55.9% among non-responders. In non-responders with low IFX levels and low IFX-Ab, the shortening of re-treatment intervals lead to significant improvement. In about 28% of patients, results of blood tests influenced treatment decisions. CONCLUSIONS: Assessment of immunogenicity of anti-TNF monoclonal antibodies proved useful information for guiding the therapy in rheumatic diseases with suboptimal clinical response. Patients with low IFX levels and low levels of IFXAb may benefit from increasing the drug dose or decreasing of re-treatment intervals. In patients with negligible serum levels of IFX and high levels of IFX-Ab, the therapy should be switched to another biological agent, probably with a different mechanism of action.

A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study.

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. RESULTS: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p<0.001), a higher frequency of digital ulcers (OR: 1.28 (1.11 to 1.47); p<0.001) and pulmonary hypertension (OR: 3.01 (1.47 to 6.20); p<0.003). In the longitudinal analysis (n=4499), after a mean follow-up of 4.9 (±2.7) years, male sex was predictive of new onset of pulmonary hypertension (HR: 2.66 (1.32 to 5.36); p=0.006) and heart failure (HR: 2.22 (1.06 to 4.63); p=0.035). 908 deaths were recorded, male sex predicted deaths of all origins (HR: 1.48 (1.19 to 1.84); p<0.001), but did not significantly account for SSc-related deaths. CONCLUSIONS: Although more common in women, SSc appears as strikingly more severe in men. Our results obtained through the largest worldwide database demonstrate a higher risk of severe cardiovascular involvement in men. These results raise the point of including sex in the management and the decision-making process.

Safety of Corticosteroid Treatment in Rheumatologic Patients With Markers of Hepatitis B Viral Infection: Pilot Evaluation Study.

BACKGROUND: Immunosuppressive agents may induce hepatitis B flares. The minimal corticosteroid dose and duration of therapy leading to HBV reactivation is unknown. OBJECTIVE: To assess whether short-term corticosteroid therapy for rheumatologic diseases induces HBV reactivation. METHODS: The records of all HBsAg or HBcore antibodies positive, anti-HBs negative patients who were hospitalized in the rheumatology department during 2001-2014 and treated with corticosteroids were reviewed. Alanine aminotransferase (ALT), HBV serology, and serum HBV DNA at baseline and 1-3 months after discharge were recorded. RESULTS: Complete data were found for 23 patients who were hospitalized 73 times for 7 days of treatment with IV corticosteroids. Eighteen patients were HBsAg positive. The mean methylprednisolone dose was 33.9 ± 24 mg/d. The concomitant therapy included DMARDs (15), low-dose corticosteroids (8), and biologicals (10). Serum HBV DNA was detected at baseline in seven patients. Three HBsAg-positive patients treated with cyclophosphamide had HBV hepatitis flare-up with elevated ALT. Two HBsAg-positive patients had reappearance of HBV DNA in serum after treatment with azathioprine and infliximab, respectively, but the ALT levels remained normal. Lamivudine therapy reduced the serum HBV DNA and improved ALT levels in all patients. Corticosteroid therapy by itself did not trigger exacerbation of HBV hepatitis. No HBV reactivation occurred in lamivudine-treated patients after recurrent exposure to biologicals or cyclophosphamide. CONCLUSIONS: Short episodes of corticosteroids seem to be safe in HBV carriers, even in the presence of DMARDs, but lamivudine prophylaxis should be considered for patients exposed to biologicals or cyclophosphamide. Larger prospective trials are needed to establish guidelines.

What tests should you use to assess small intestinal bacterial overgrowth in systemic sclerosis?

OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) plays a major role in the pathogenesis of malabsorption in SSc patients and is a source of great morbidity and even mortality, in those patients. This manuscript reviews which tests are valid and should be used in SSc when evaluating SIBO. METHODS: We performed systematic literature searches in PubMed, Embase and the Cochrane library from 1966 up to November 2014 for English language, published articles examining bacterial overgrowth in SSc (e.g. malabsorption tests, breath tests, xylose test, etc). Articles obtained from these searches were reviewed for additional references. The validity of the tests was evaluated according to the OMERACT principles of truth, discrimination and feasibility. RESULTS: From a total of 65 titles, 22 articles were reviewed and 20 were ultimately extracted to examine the validity of tests for GI morphology, bacterial overgrowth and malabsorption in SSc. Only 1 test (hydrogen and methane breath tests) is fully validated. Four tests are partially validated, including jejunal cultures, xylose, lactulose tests, and 72 hours fecal fat test. CONCLUSIONS: Only 1 of a total of 5 GI tests of bacterial overgrowth (see above) is fully validated in SSc. For clinical trials, fully validated tests are preferred, although some investigators use partially validated tests (4 tests). Further validation of GI tests in SSc is needed.

Periodontal Conditions and Tumor Necrosis Factor-Alpha Level in Gingival Crevicular Fluid of Scleroderma Patients.

BACKGROUND: Systemic sclerosis (SSc) is a chronic disease with prominent vasculopathy, inflammation, production of autoantibodies, and tissue fibrosis. Periodontitis is a chronic inflammatory oral condition manifesting as microbial infection, inflammation and destruction of the alveolar bone. In both conditions tumor necrosis factor-alpha (TNFα) and other proinflammatory cytokines play an important role in pathogenesis. OBJECTIVES: To assess the periodontal status in SSc patients and compare these parameters to TNFα level in gingival crevicular fluid (GCF) of SSc patients and healthy controls. METHODS: Twenty SSc patients and 20 controls underwent periodontal examination, including probing depth (PD), plaque index (PI), gingival-index (GI), bleeding on probing (BOP), and measurement of TNFα levels in collected GCF. RESULTS: SSc patients had a greater PD (3.74 ± 0.32 mm vs. 3.35 ± 0.31 mm, P > 0.003), GI (1.53 ± 0.34 vs. 1.12 ± 0.54, P > 0.049), and non-significantly higher BOP than controls. TNFα levels in GCF were higher in SSc patients (1.63 ± 0.36 vs. 1.15 ± 0.34 pg/ml, P = 0.001). Periodontitis parameters correlated with several SSc variables; PI in particular was higher in patients with longer disease duration, sclerodactyly, more severe skin involvement, and SSc activity score. CONCLUSIONS: Patients with SSc have higher indices of periodontal inflammation and higher TNFα level in GCF than did healthy individuals. These changes probably reflect the complexity of factors that influence oral health in SSc. Common pathologic pathways may be responsible for the association between SSc and periodontitis, which requires further study.

Long-term follow-up of patients with scleroderma interstitial lung disease treated with intravenous cyclophosphamide pulse therapy: a single-center experience.

BACKGROUND: Scleroderma lung disease (ILD-SSc) is treated mainly with cyclophosphamide (CYC). The effectiveness of CYC was judged after 12-24 months in most reports. OBJECTIVES: To analyze the effect of monthly intravenous CYC on pulmonary function tests including forced vital capacity (FVC) and diffusing lung capacity (DLCO), as well as Rodnan skin score (mRSS), during long-term follow-up. METHODS: We retrospectively collected the data on 26 ILD-SSc patients who began CYC treatments before 2007. Changes in FVC, DLCO and mRSS before treatment, and at 1,4 and 7 years after completion of at least six monthly intravenous CYC treatments for ILD-SSc were analyzed. RESULTS: Mean cumulative CYC dose was 8.91 ± 3.25 G. More than 30% reduction in FVC (0%, 8%, and 31% of patients), DLCO (15%, 23%, 31%), and mRSS (31%, 54%, 62%) at years 1, 4 and 7 was registered. During the years 0-4 and 4-7, annual changes in FVC, DLCO and mRSS were 3.2 vs. 0.42% (P < 0.040), 4.6 vs. 0.89% (P < 0.001), and 1.8 vs. 0.2 (P = 0.002). The greatest annual FVC and DLCO reduction over the first 4 years correlated with mortality (P = 0.022). There were no differences in the main variables regarding doses of CYC (< 6 G and > 6 G). CONCLUSIONS: In patients with ILD-SSc, CYC stabilized the reduction of FVC during treatment, but this effect was not persistent. The vascular characteristic of ILD-SSc (DLCO) was not affected by CYC treatment. CYC rapidly improved the mRSS. This effect could be achieved with at least 6 G of CYC. Higher rates of annual reduction in FVC and DLCO in the first 4 years indicate the narrow window of opportunity and raise the question regarding ongoing immunosuppression following CYC infusions.

Is cyclophosphamide still the gold standard in early severe rapidly progressive systemic sclerosis?

Cyclophosphamide (CYC) has been a gold standard of treatment for severe progressive Systemic Sclerosis (SSc), especially in patients with concomitant interstitial lung disease (ILD). This approach was based on results of several interventional studies, including randomized control trials, which mainly addressed SSc-ILD as a primary end point and skin involvement as a second one. The use of CYC is time-limited due to significant adverse events. More recently, other immunosuppressive and biological agents showed efficacy but better safety profile in patients with SSc and SSc-ILD. With regards to other end-points, post-hoc analyses, systematic reviews and metalysis showed that CYC had limited influence on patients' quality of life, event-free survival and mortality. Comprehensive patient's stratification according to a molecular, cellular and phenotypic pattern may help in choosing of personalized medicine with more ambitious treatment effect and should be the future direction. According to the above available data and even if scientific evidence may be missing, experts' opinion has changed the attitude to CYC as an anchor drug in the management of severe SSc. Indeed, CYC has been pushed to the second and even third treatment option after mycophenolate mofetil, tocilizumab or rituximab. This position became obvious during debate on this topic at CORA meeting 2023.